title: Untangling structure-function relationships in the rhomboid family of intramembrane proteases.
abstract: Rhomboid proteases are a family of integral membrane proteins that have been implicated in critical regulatory roles in a wide array of cellular processes and signaling events. The determination of crystal structures of the prokaryotic rhomboid GlpG from Escherichia coli and Haemophilus influenzae has ushered in an era of unprecedented understanding into molecular aspects of intramembrane proteolysis by this fascinating class of protein. A combination of structural studies by X-ray crystallography, and biophysical and spectroscopic analyses, combined with traditional enzymatic and functional analysis has revealed fundamental aspects of rhomboid structure, substrate recognition and the catalytic mechanism. This review summarizes these remarkable advances by examining evidence for the proposed catalytic mechanism derived from inhibitor co-crystal structures, conflicting models of rhomboid-substrate interaction, and recent work on the structure and function of rhomboid cytosolic domains. In addition to exploring progress on aspects of rhomboid structure, areas for future research and unaddressed questions are emphasized and highlighted. This article is part of a Special Issue entitled: Intramembrane Proteases.
authors.affiliation: Membrane Protein Disease Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
authors.forename: Cory L
authors.initials: CL
authors.lastname: Brooks
authors.forename: M Joanne
authors.initials: MJ
authors.lastname: Lemieux
mesh_terms: D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D002462:Cell Membrane / Q000737:chemistry* / Q000201:enzymology; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006193:Haemophilus influenzae / Q000737:chemistry / Q000201:enzymology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C102898:GlpG protein, E coli; D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D010450:Endopeptidases
keywords: GlpG; Intramembrane protease; Membrane protein structure; Rhomboid protease; Serine protease; X-ray crystallography